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Review
. 2019 Oct 24:8:F1000 Faculty Rev-1793.
doi: 10.12688/f1000research.18872.1. eCollection 2019.

Emerging approaches to target mitochondrial apoptosis in cancer cells

Andrew Gilmore  1 , Louise King  1
Affiliations
Review

Emerging approaches to target mitochondrial apoptosis in cancer cells

Andrew Gilmore et al. F1000Res. .

Abstract

Apoptosis is a highly conserved programme for removing damaged and unwanted cells. Apoptosis in most cells is coordinated on mitochondria by the Bcl-2 family of proteins. The balance between pro- and anti-apoptotic Bcl-2 family proteins sets a threshold for mitochondrial apoptosis, a balance that is altered during cancer progression. Consequently, avoidance of cell death is an established cancer hallmark. Although there is a general perception that tumour cells are more resistant to apoptosis than their normal counterparts, the realities of cell death regulation in cancer are more nuanced. In this review we discuss how a profound understanding of this control has led to new therapeutic approaches, including the new class of BH3-mimetics, which directly target apoptosis as a vulnerability in cancer. We discuss recent findings that highlight the current limitations in our understanding of apoptosis and how these novel therapeutics work.

Keywords: Apoptosis; BH3-mimetics; cancer.

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Conflict of interest statement

No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.

Figures

Figure 1.
Figure 1.. The canonical interactions between Bcl-2 family protein subgroups.
The Bcl-2 family of proteins consists of three groups: anti-apoptotic proteins (for example, Bcl-2, Bcl-XL, Bcl-W and Mcl-1), pore-forming pro-apoptotic proteins (for example, Bax and Bak) and the BH3-only proteins. The BH3-only subgroup shows distinct binding preferences for both anti- and pro-apoptotic Bcl-2 proteins. Some BH3-only proteins, such as Noxa and Bad, bind only specific anti-apoptotic proteins. As such, they do not directly activate Bax and Bak and are termed “sensitizer” BH3-only proteins. Other BH3-only proteins, including Bim, Bid and PUMA, can bind both anti- and pro-apoptotic proteins. These either can activate pro-apoptotic Bax and Bak (and thus are termed “direct activators”) or can be inhibited by binding the anti-apoptotic proteins. The BH3-domain of the BH3-only proteins represents a canonical site of interaction with the other subgroups. BH3-mimetics such as ABT-263, ABT-199 and S63845 have been developed to mimic the interaction of specific BH3-only proteins with anti-apoptotic proteins.
Figure 2.
Figure 2.. Apoptotic priming describes the proximity of a cell to the point of commitment to mitochondrial outer membrane permeabilisation (MOMP).
Cells can exist in different states of priming, which essentially describes how close the cell lies to MOMP, which is dependent upon the functional Bcl-2 protein landscape in that cell. Normal cells can shift their state of priming following changes in cellular stress or exposure to pro-apoptotic stimuli, such as DNA damage or growth factor deprivation. These signals result in changes in the degree of priming, although this may not result in MOMP. Normal cells are often insensitive to BH3-mimetics. In contrast, cancer cells are often primed and closer to MOMP. Overexpression of anti-apoptotic Bcl-2 proteins in cancer cells can suppress MOMP by sequestering pro-apoptotic Bcl-2 family members. However, this results in them being extremely sensitive to BH3-mimetics, which can compete with the pro-apoptotic proteins, releasing them from their anti-apoptotic partners to drive MOMP .
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